Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma
Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma
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Nanog 通过胰岛素样生长因子途径调节人肝细胞癌中癌症干细胞的自我更新
DOI：
10.1002/hep.25745
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发表时间：
2012-09-01
期刊：
影响因子：
13.5
通讯作者：
Qian, Cheng
中科院分区：
文献类型：
--
作者：
Shan, Juanjuan;Shen, Junjie;Qian, Cheng
肝细胞癌（HCC）表现出细胞异质性，胚胎干细胞相关基因在低分化肿瘤的一部分癌细胞中优先过表达。然而，目前尚不清楚这些癌细胞是否或如何促进肿瘤的发生和发展。在这里，我们的数据显示，癌细胞中多能转录因子Nanog的表达增加与HCC的临床预后较差相关。使用Nanog启动子作为报告系统，我们可以成功地分离出一小部分Nanog阳性细胞亚群。我们证明nanog阳性细胞表现出增强的自我更新能力、克隆原性和肿瘤起始能力，这与癌症干细胞（CSCs）定义中的关键标志一致。在体外和体内条件下，NanogPos CSCs均可分化为成熟的癌细胞。此外，我们发现NanogPos CSCs对治疗剂（例如索拉非尼和顺铂）具有耐药性，并且具有较高的肿瘤侵袭和转移能力。Nanog在NanogPos CSCs中表达下调可导致自我更新能力下降，并伴有干细胞相关基因的表达下降和成熟肝细胞相关基因的表达增加。Nanog在NanogNeg细胞中过表达可以恢复自我更新。此外，我们发现胰岛素样生长因子（IGF）2和IGF受体（IGF1R）在NanogPos CSCs中上调。NanogPos CSCs中Nanog的低表达抑制了IGF1R的表达，而NanogNeg细胞中Nanog的过表达增加了IGF1R的表达。IGF1R信号的特异性抑制剂可以显著抑制自我更新和Nanog的表达，表明IGF1R信号参与了Nanog介导的自我更新。结论：这些数据表明Nanog可能是HCC中CSCs的一种新的生物标志物，并且Nanog可能通过igf1r信号通路在维持CSCs的自我更新中发挥关键作用。(肝脏病学2012;56:10041014)
Hepatocellular carcinoma (HCC) exhibits cellular heterogeneity and embryonic stem-cellrelated genes are preferentially overexpressed in a fraction of cancer cells of poorly differentiated tumors. However, it is not known whether or how these cancer cells contribute to tumor initiation and progression. Here, our data showed that increased expression of pluripotency transcription factor Nanog in cancer cells correlates with a worse clinical outcome in HCC. Using the Nanog promoter as a reporter system, we could successfully isolate a small subpopulation of Nanog-positive cells. We demonstrate that Nanog-positive cells exhibited enhanced ability of self-renewal, clonogenicity, and initiation of tumors, which are consistent with crucial hallmarks in the definition of cancer stem cells (CSCs). NanogPos CSCs could differentiate into mature cancer cells in in vitro and in vivo conditions. In addition, we found that NanogPos CSCs exhibited resistance to therapeutic agents (e.g., sorafenib and cisplatin) and have a high capacity for tumor invasion and metastasis. Knock-down expression of Nanog in NanogPos CSCs could decrease self-renewal accompanied with decreased expression of stem-cellrelated genes and increased expression of mature hepatocyte-related genes. Overexpression of Nanog in NanogNeg cells could restore self-renewal. Furthermore, we found that insulin-like growth factor (IGF)2 and IGF receptor (IGF1R) were up-regulated in NanogPos CSCs. Knock-down expression of Nanog in NanogPos CSCs inhibited the expression of IGF1R, and overexpression of Nanog in NanogNeg cells increased the expression of IGF1R. A specific inhibitor of IGF1R signaling could significantly inhibit self-renewal and Nanog expression, indicating that IGF1R signaling participated in Nanog-mediated self-renewal. Conclusion: These data indicate that Nanog could be a novel biomarker for CSCs in HCC, and that Nanog could play a crucial role in maintaining the self-renewal of CSCs through the IGF1R-signaling pathway. (HEPATOLOGY 2012;56:10041014)